Intermediates in the synthesis of (±)-camptothecin and related compounds and synthesis thereof

ABSTRACT

An A-ring substituted chemical compound has the formula                    
     wherein Y is —CR 3 , R 1 , R 2 , R 3  and R 6  are, independently, hydrogen, an allyl group, a benzyl group, a propargyl group, an alkoxyl group, a halogen, a haloalkyl group, an amino group, or a cyano group, R 4  is an alkyl group, an allyl group, a propargyl group or a benzyl group, and R 5  is an alkyl group, or a benzyl group.

This is a divisional of application Ser. No. 08/609,900 filed on Mar. 4,1996, U.S. Pat. No. 5,744,605 which is a continuation application ofapplication Ser. No. 08/085,190 filed Jun. 30, 1993.

GOVERNMENT INTERESTS

This invention was made with government support under grant number RO1GM33372 awarded by the National Institutes of Health. The government hascertain rights in this invention.

FIELD OF THE INVENTION

The present invention relates to novel intermediates in the synthesis of(±)-camptothecin and related compounds, and to a synthesis ofcamptothecin and related compounds via a 4+1 radical annulation.

BACKGROUND OF THE INVENTION

As part of an antitumor screening program, Wall and coworkers identifiedthe novel pyrrolo [3,4-b] quinoline alkaloid (S)-camptothecin in 1966.Wall, M. E., et al., J. Am. Chem. Soc., 88, 3888 (1966); Carte, B. K.,et al., Tetrahedron, 46, 2747 (1990). The chemical formula of(S)-camptothecin is provided below.

This compound had been isolated from the extracts of the camptothecaacuminata tree. In addition to its novel structure, camptothecin has twoother unusual features: its quinoline nitrogen is not very basic, andits α-hydroxy lactone is quite reactive. For a few years, camptothecinappeared to be an exciting lead compound for cancer chemotherapy.However, initial medical excitement waned because of the relativeinsolubility of camptothecin. Moreover, clinical trials of awater-soluble sodium salt derived by opening the lactone of camptothecinwere abandoned because of unpredictable toxicity problems. The sodiumsalt is considerably less potent than camptothecin and its activity isnow thought to result from lactonization to reform camptothecin in vivo.

Camptothecin was synthesized about ten times during the 1970s, althoughsome later syntheses are modifications of earlier ones. Syntheses basedon the Friedlander quinoline synthesis to construct ring B were mostcommon. Ejima, A., et al., J. Chem. Soc., Perkin Trans. 1, 27 (1990);Earl, R. E. and Vollhardt, K. P. C., J. Org. Chem. 1984, 49, 4786;Ihara, M. et al., J. Org. Chem., 48,3150 (1983); Cai, J. C. andHutchinson, C. R., Chem, Heterocycl. Compd. 25, 753 (1983); Hutchinson,C. R., Tetrahedron 37, 1047 (1981); Cai, J. C. and Hutchinson, C. R.,The Alkaloids: Chemistry and Pharmacol; Brossi, A. Ed.; Academic Press:New York, Vol. 21, p. 101 (1983); Schultz, A. G., Chem. Rev. 73, 385(1973). Many syntheses are racemic, but resolutions have been reported.See Wani, M. C., et al. J. Med. Chem., 30, 2317 (1987). More recently, achiral auxiliary approach to asymmetric ethylation was described. SeeEjima, A., et al., Tetrahedron Lett., 30, 2639 (1989). Following themedicinal lead, synthetic interest in camptothecin peaked in the late70s, and then began to wane.

Oncological and medicinal interest in camptothecin was reborn in the mid80s when details about camptothecin's unique mechanism of action beganto unfold. Camptotlecin acts on DNA through the intermediacy of theenzyme topoisomerase I. Hsiang, Y. H., et al., J. Biol. Chem, 260,14873(1985); Hsiang, Y. H. and Liu, L. F., Cancer Res., 48, 1722 (1988); Liu,L. F., Annu. Rev. Biochem., 58, 351 (1989); “Chemotherapy:Topoisomerases as Targets,” Lancet, 335, 82 (1990).

The topoisomerases solve topological problems of DNA. Humantopoisomerase I (100 kd) catalyzes the relaxation of supercoiled DNA bycleaving a single phosphodiester bond to form a temporary phosphoryltyrosine diester. This intermediate is called the “cleavable complex.”The other end of the cleaved strand is free, and can “unwind” before theDNA chain is resealed by reverse of the original reaction. TopoisomeraseI acts without cofactors, its reactions are fully reversible, and it isthought to be especially important for unwinding DNA (thermodynamicallyfavorable) during replication. In contrast, topoisomerase II acts bycleaving the resealing (after strand passage) both strands of DNA, andits reactions are coupled with ATP hydrolysis.

There is now very strong evidence that camptothecin kills cells bybinding to and stabilizing the covalent DNA-topoisomerase I complex inwhich one strand of DNA is broken (the cleavable complex). Theprogression from the ternary camptothecin/topoisomerase I/DNA complex tocell death is not well understood, and is the subject of intenseinvestigation. Several lines of evidence (including the completereversibility of ternary complex formation) indicate that the ternarycomplex does not simply tie up DNA, but itself actively initiates celldeath. For this reason, camptothecin is often called a “topoisomerasepoison.”

Until very recently, camptothecin and its close relatives were the onlyknown topoisomerase I poisons. In contrast, there are now many knownantitumor agents that are topoisomerase II poisons. These include largeclasses of intercalators like the acridines and anthracyclines that wereoriginally thought to interact only with DNA. Such topoisomerase IIpoisons may be inherently less selective than camptothecin because theirinteractions with DNA do not require topoisomerase II. Importantnon-intercalative topoisomerase II poisons include members of thepodophyllotoxin class.

Camptothecin is being touted as an unusually important lead in cancerchemotherapy because of its selectivity. The (potential) selectivetoxicity of camptothecin towards cancer cells emanates from twosources: 1) camptothecin is highly selective for the DNA/topoisomerase Icleavable complex, and 2) replicating cancer cells contain elevatedlevels of topoisomerase I (15-fold increases over normal cells haverecently been measured).

Recent tests in xenografts by Potmesil and coworkers were verypromising. See Giovanella, B. C., et al., Science, 246, 1046 (1989).Racemic 9-aminocamptothecin was found to be very effective in treatingmice carrying colon cancer xenografts. Indeed most of the mice in thestudy were cured by 9-aminocamptothecin at dose levels that were welltolerated. The improved efficacy of 9-aminocamptothecin compared tocurrent drugs used in colon cancer chemotherapy (like 5-fluorouracil)was dramatic. 10,11-Methylenedioxycamptothecin also showed very goodpromise. Though it is still early, the significance of these results isvery high. Human colon cancer is a major problem in clinical oncology,and one in twenty-five Americans will develop this disease during theirlifetime.

Recent results are even more encouraging. See Giovanella, B. C., et al.,Cancer Res., 51, 3052 (1991). It has been discovered that(S)-camptothecin itself can be formulated in 20% interlipid, and thatthis formulation is active both intramuscularly and orally. Thesetreatments were far superior to the intravenous ones. With thisformulation, non-toxic doses of camptothecin suppressed growth andinduced regression of cancer in thirteen human xenograft lines includingcolon, lung, breast, stomach, ovary, and malignant melanoma.Camptothecin was much less toxic than its sodium salt, and was moreeffective than any other clinical drug tested.

Other close relatives of camptothecin are also emerging as excellentcandidates for chemotherapy against a variety of tumor types. Severalsuch compounds are undergoing clinical trials. Curran, D. P., “TheCamptothecins: A Reborn Family of Antitumor Agents,” J. of the ChineseChem, Soc. 40, 1-6 (1993), the disclosure of which is incorporatedherein by reference. S Sawada, S., Chem. Pharm. Bull., 39, 1446 (1991);Giovanella, B. C., et al., Science (Washington, D.C.), 246, 1046 (1989);Kingsbury, W. D., et al.; Med. Chem., 34, 98 (1991); Sawada, S., et al.;Chem. Pharm. Bull., 39,1446 (1991), Nicholas, A. W., et al. J. Med.Chem. 33, 972 (1991).

The excitement about camptothecin recently increased to even greaterlevels upon the discovery that it is a potent antiretroviral agent.Preil and coworkers showed that camptothecin and relatives: 1) inhibitedretroviral topoisomerase I, 2) prevented retroviral infections inhealthy cells, 3) reduced and eliminated retroviral infections andinfected cells, and 4) did not harm cells at useful dose levels. Priel,E., et al., AIDS Res. Hum. Retroviruses 7, 65 (1991). Topoisomerase IIinhibitors were ineffective. These results suggest that camptothecin mayrepresents a new avenue of investigation for the potential treatment ofAIDS.

Given the current interest in camptothecins, new directions in the totalsynthesis of this family of compounds would be welcome.

SUMMARY OF THE INVENTION

Accordingly, the present invention provides a short, convergent totalsynthesis of (±)-camptothecin and related compounds using a novel 4+1radical annulation followed by another cyclization to simultaneouslyassemble rings B and C of camptothecin and related compounds.

Generally, the present invention provides a method of synthesizingtetracyclic compounds having the general formula

which are intermediates in many syntheses of (+)camptothecin and relatedcompounds. The conversion of these intermediates to (±)-camptothecin andrelated compounds is accomplished in two steps: hydroxymethylation andoxidation.

The synthesis of the tetracyclic intermediates comprises the step of a4+1 radical annulation wherein the following novel precursor:

is reacted with an aryl isocyanide such as phenyl isocyanide. Y ispreferably selected from the group consisting of —N and —CR³. The aryliscyanide may be unsubstituted, monosubstituted, disubstituted ortrisubstituted.

R¹, R², R³ and R⁶are preferably selected from the following groups:hydrogen, normal and branched alkyl groups, haloalkyl groups,perfluoroalkyl groups, allyl groups, benzyl groups, propargyl groups,alkoxyl groups, halo groups, substituted amino groups, substitutedacylamino groups, cyano groups, acyl groups, substituted hydroxy alkylgroups, substituted amino alkyl groups. R⁴ is preferably selected fromprimary or secondary alkyl, allyl, propargyl and benzyl groups. R⁵ ispreferably selected from linear or branched alkyl groups or benzylgroups. Most preferably, R⁵ is selected from linear or branched alkylgroups in the range of C₁ to C₆.

The present synthetic route is useful for large-scale production ofcamptothecin and the production of new analogs of camptothecin forevaluation of biological activity.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is an illustration of the reaction scheme for a model 4+1 radicalannulation.

FIG. 2 is an illustration of a synthetic scheme for the synthesis ofcamptothecin via a 4+1 radical annulation.

FIG. 3 is an illustration of the general synthetic scheme of the present4+1 radical annulation.

FIGS. 4a-4 g provide illustrations of the chemical structures of severaltetracyclic intermediates.

FIG. 5 is an illustration of a novel camptothecin analogue.

FIG. 6 provides an illustration of a model synthetic scheme for a noveltetracycle.

FIG. 7 provides a synthetic scheme for a novel precursor.

FIG. 8 provides an illustration of the synthetic scheme for a noveltetracycle intermediate.

FIG. 9 provides an illustration of synthetic schemes for preparing arylisocyanides.

DETAILED DESCRIPTION OF THE INVENTION Model Reaction

The viability of the key 4+1 annulation was first demonstrated in themodel reaction shown in FIG. 1.

In the reaction of FIG. 1, readily available bromopyridone 2 wasN-propargylated to give 3. The synthesis of bromopyridone 2 is describedin Newkome, G. R., et al, Synthesis 707 (1974), the disclosure of whichis incorporated herein by reference. In turn, 3 reacted with phenylisocyanide under conditions similar to those developed for reactions ofsimple pentynyl iodides. These conditions are detailed in Curran, D. P.and Liu, H., J. Am. Chem, Soc. 113, 2127 (1991), the disclosure of whichis incorporated herein by reference.

Generally, an 80° C. benzene solution of 3 (1 equiv), phenyl isocyanide(PhNC) (5 equiv), and hexamethylditin (1.5 equiv) was irradiated with asunlamp for 8 hr. After chromatography, the known tetracycle 4 wasisolated in 40% yield as a white solid.

FIG. 1 also shows a hypothetical mechanism for the conversion of 3 to 4.Addition of pyridone radical 5 to phenyl isocyanide to give 6 isfollowed by two radical cyclizations and an oxidative rearomatization.Curran, D. P. and Liu, H., J. Am. Chem. Soc., 113, 2127 (1991);Leardini, R. et al., J. Org. Chem., 57, 1842 (1992); Bowman, W. R. etal., Tetrahedron, 47,10119 (1991), the disclosures of which areincorporated herein by reference. See also Stork, G.; Sher, M. M., J.Am. Chem. Soc., 105, 6765 (1983); Barton, D. H. R.; Ozbalik, N.; Vaher,B. Tetrahedron, 44, 3501 (1988).

Synthesis of (±)-Camptothecin

The formal total synthesis of (±)-camptothecin is shown in FIG. 2.Nitrile 8 (dimethyl 3-(cyanomethylidene)pentanedioate) was firstprepared by standard Doebner condensation of dimethylacetonedicarboxylate and cyanoacetic acid (70%). See Simchen, G., Chem.Ber., 103, 389 (1978). A flask equipped with a Dean-Stark waterseparator was charged with benzene (60 mL), dimethylacetone-1,3-dicarboxylate (34.8 g, 0.2 mol), cyanoacetic acid (18.7 g,0.22 mol), acetic acid (5.4 g, 0.09 mol), and ammonium acetate (3.1 g,0.04 mol). The mixture was stirred for 5 minutes and then heated with anoil bath (oil temperature 130-135° C.) until no more water wascollected. Heating time was generally 6 hours and the water layercollected was around 6 mL. After the mixture was cooled to roomtemperature, cold water was added. This mixture was then extracted twicewith ether. The combined organic phase was washed with water, saturatedsodium bicarbonate solution, and brine, and dried over sodium sulfate.After removal of solvent, the crude product was purified by vacuumdistillation to give 1.5 g of dimethyl acetone-1,3-dicarboxylate, and27.2 g of nitrile 8 (104-124° C./0.03 mm) as colorless liquid, yield69-72%. Nitrile 8 was characterized as follows: ¹H NMR (300 MHz, CDCl₃)δ 5.43 (1H, s), 3.57 (3H, s), 3.55 (3H, s), 3.45 (2H, s), 3.26 (2H, s);¹³C NMR (75 MHz, CDC13) δ 168.8, 168.5, 151.7, 115.2, 102.6, 52.0 (2 C),40.5, 38.8; IR (neat) 2224, 1738 cm⁻¹.

Standard saponification (KOH/EtOH) gave diacid 9. Conversion of diacid 9to bromopyridone 10 (methyl 2-(6-bromo-2(1H)-pyridon-4-yl) acetate) wasaccomplished by modification of a known method to preparechloropyridones. The diacid was first treated with PCl₅, and thengaseous HBr (10 equiv) was introduced. See Simchen, G., Chem. Ber., 103,389 (1978).

In general, potassium hydroxide (10 g, 180 mmol) was added to a 0° C.solution of nitrile 8 (7.88 g, 40 mmol) in ethanol (160 mL) withstirring. The reaction mixture was stirred at room temperature (“RT”)for 2 days. After solvent removal, ice-water (100 mL) was added. Thenthe mixture was immersed in an ice-water bath, and 6 N HCl was addedslowly until the pH value reached to 1. This solution was saturated withsodium chloride, and extracted with ethyl acetate (70 mL×4). Thecombined organic phase was dried over sodium sulfate. After solventremoval under reduced pressure (via rotary evaporation and vacuumpumping), 6.87 g of 3-(cyanomethylidene) pentanedioic acid 9 wascollected as yellow or orange solids.

These solids were crushed to powders and methylene chloride (270 mL) wasadded. The mixture was cooled to 0° C. and charged with phosphoruspentachloride (17.1 g, 82 mmol) under argon. The suspension was stirredat room temperature until all the white solids dissolved (3-9 h). Theflask was cooled with an acetone-dry-ice bath, evacuated with anaspirator, and sealed.

Gaseous anhydrous hydrogen bromide (about 10 L, 400 mmol) was introducedand absorbed by the solution. The vacuum was then released by fillingthe vessel with argon. The flask was equipped with a drying-tube whichwas connected to a gas trap to absorb excess HBr. The solution wasstirred at −78° C. for 1 h and at room temperature for 8 h. The reactionmixture was cooled to −78° C. again. Anhydrous methanol (15.4 g, 480mmol) was added in one portion. The solution was then slowly warmed toroom temperature and stirred for 2 more hours. After addition ofice-water (150 mL), two layers were separated. The aqueous layer wasextracted with methylene chloride (100 mL×2). The combined organic phasewas dried over sodium sulfate. After removal of solvent, the residue wasapplied to chromatography (silica gel, CHCl₃/EtOAC) to give 6.2 g ofbromopyridone 10 as off-white solids, yield 63% (from nitrile 8). Theproduct contained 3-8% of the 6-chloro analogue as detected by GC. ¹HNMR (300 MHz, CDCl₃) δ 11.82 (1H, Br), 6.81 (1H, d, J=0.8 Hz), 6.60 (1H,d, J=0.8 Hz), 3.73 (3H, s), 3.53 (2H, s); ¹³C NMR (75 MHz, CDCl₃) δ169.7, 165.1, 149.4, 132.0, 117.6, 113.5, 52.6, 40.3; IR (neat) 1728,1647, 1592, 1451 cm⁻¹; MS (m/e) 247 (M), 245 (M), 188, 186, 166 (basepeak); HRMS calcd for CaH₈O₃BrN 244.9687, found 244.9661.

N-Propargylation (70%) and C-ethylation (95%) then gave the precursor 11for the 4+1 annulation. For C-ethylation, see Danishefsky, S. andEtheredge, S. J., J. Org. Chem., 39, 3430 (1974), the disclosure ofwhich is incorporated herein by reference.

In general, the solution of bromopyridone 10 (12.3 g, 50 mmol) inanhydrous ethylene glycol dimethyl ether (DME, 150 mL) was cooled to 0°C. to −10° C. Sodium hydride (60% suspension in mineral oil, 2.2 g, 55mmol) was added in several portions under argon. The mixture was warmedto room temperature and stirred until hydrogen ceased to evolve (about20 min at room temperature). Anhydrous lithium bromide (4.8 g, 55 mmol)was added. After 20 minutes, propargyl bromide (80% in toluene, 11.9 g,100 mmol) and DMF (3.7 g, 50 mmol) were added. The mixture was heated at65° C. for 16 hours. After solvent removal, methylene chloride and waterwere added to the residue. The organic layer was separated. The aqueouslayer was extracted with methylene chloride. The combined organic phasewas washed with water and brine, and dried over sodium sulfate. Aftersolvent removal with a rotary evaporator, a small amount of ether wasadded to the residue, and solids precipitated. The solids were filteredand rinsed with ether to give approximately 9.34 g of methyl2-(6-bromo-N-propargyl-2(1H)-pyridon-4-yl) acetate. The filtrate wasconcentrated and applied to column chromatography (silica gel,hexane/ethyl acetate) to give additional 1.1 g of the product asoff-white solids. Total yield was 69-73%. The product contained 3-8% ofthe 6-chloro analogue as detected by GC. ¹H NMR (300 MHz, CDCl₃) δ 6.50(1 H, d, J=1.6 Hz), 6.43 (1H, d, J=1.6 Hz), 5.02 (2H, d, J=2.4 Hz), 3.72(3H, s), 3.40 (2H, s), 2.29 (1H, t, J=2.4 Hz); ¹³C NMR (75 MHz, CDCl₃) δ169.6, 161.7, 146.7, 126.3, 118.9, 112.9, 76.9, 72.6, 52.5, 40.1, 38.2;IR (neat) 3287, 1734, 1655, 1597 cm⁻¹; MS (m/e) 285 (M), 283 (M, basepeak), 226, 224, 204, 176, 116; HRMS calcd for C₁₁H₁₀O₃BrN 282.9844,found 282.9850.

Under argon, methyl 2-(6-bromo-N-propargyl-2(1H)-pyridon-4-yl) acetate(852 mg, 3 mmol) was dissolved in DME (15 mL). The solution was cooledto −60° C., and potassium tert-butoxide (353 mg, 3.15 mmol) was added.After 5 min at −60° C., the mixture was warmed to −15° C., then cooledto −60° C. again. Ethyl iodide (1.87 g, 12 mmol) was added. After 5minutes at −60° C., the reaction mixture was kept in an ice-bath, andstirred overnight (0° C. to room temperature). Solvent was removed witha rotary evaporator. Methylene chloride (30 mL) and water (30 mL) wereadded. The organic layer was separated. The aqueous layer was extractedwith methylene chloride. The combined organic phase was washed withbrine, and dried over sodium sulfate. After solvent removal, the residuewas applied to column chromatography (silica gel, chloroform) to give890 mg of precursor 11a (methyl2-(6-bromo-N-propargyl-2(1H)-pyridon-4-yl) butyrate) in 95% yield. Theproduct contained 5-10% of the 6-chloro analogue as detected by GC. ¹HNMR (300 MHz, CDCl₃) δ 6.52 (1H,d,J=1.7Hz),6.44(1H, d,J=1.7Hz), 5.01(2H,d,J=2.4H),3.69 (3H, s), 3.22 (1H, t, J=7.6 Hz), 2.30 (1H, t, J=2.4Hz), 2.00 (1H, m), 1.72 (1H, m), 0.90 (3H, t, J=7.4 Hz); ¹³C NMR (75MHz, CDCl₃) δ 172.2, 161.7, 151.4, 126.3, 117.8, 111.3, 76.8, 72.5, 52.4(2 C), 38.2, 25.3, 11.9; IR (neat) 3264, 1732, 1663, 1509 cm⁻¹; MS (m/e)313 (M, base peak), 311, 284, 282, 254, 252, 232, 204, 144; HRMS calcdfor C₁₃H₁₄O₃BrN 311.0157, found 311.0139.

Reaction of 11a with phenyl isocyanide as described above gave pure 12ain 45% isolated yield.

Compound 12a was first prepared by Danishefsky, and has been a keyintermediate in many syntheses of camptothecin. See Volkmann, R.Danishefsky, S., Eggler, J. and Soloman, D. M., J. Am. Chem. Soc., 93,5576 (1971); Cai, J. C. and Hutchinson, C. R., Chem. Heterocycl. Compd.,25, 753 (1983); Hutchinson, C. R., Tetrahedron, 37, 1047 (1981); Cai, J.C. and Hutchinson, C. R., The Alkaloids: Chemistry and Pharmacology,Brossi, A. Ed., Academic Press: New York, Vol. 21, p. 101 (1983); andSchultz, A. G., Chem. Rev. 73, 385 (1973), the disclosures of which areincorporated herein by reference. Conversion of 12a to (±)-camptothecinis accomplished in two steps: hydroxymethylation (35%) and oxidation(quantitative). See Cai, J. C. and Hutchinson, C. R., Chem. Heterocycl.Compd., 25, 753 (1983); Hutchinson, C. R., Tetrahedron, 37, 1047 (1981);Cai, J. C. and Hutchinson, C. R., The Alkaloids: Chemistry andPharmacology, Brossi, A. Ed., Academic Press: New York, Vol.21, p.101(1983); and Schultz, A. G., Chem. Rev. 73, 385 (1973), the disclosuresof which are incorporated herein by reference.

This synthesis of the key Danishefsky tetracycle 12a under the presentmethod requires only six steps starting from dimethylacetonedicarboxylate, and the overall yield is currently approximately13%.

A number of analogs of tetracycle 12a can be prepared under the presentsynthesis scheme. The general chemical equation for the 4+1 annulationof the present invention is given in FIG. 3. In FIG. 3, X of precursor11 preferably comprises Cl, Br, or I. Y of precursor 11 may comprise N,or C—R³. Regioisomers are possible when R² of tetracyclic intermediates12 does not comprise hydrogen.

Several examples of preparation of tetracyclic intermediates via thepresent 4+1 annulation involving precursor 11 and an aryl isonitrile areprovided below.

Preparation of Tetracyclic Intermediates EXAMPLE 1

Under the general procedure, a benzene solution of precursor 11a (methyl2-(6-bromo-N-propargyl-(1H)-pyridon-4yl)butyrate), phenyl isocyanide(1.5 to 5 equiv) and hexamethyiditin (0.7 to 1.5 equiv) in a flask (flatflask preferred) was irradiated under argon with a 275W GE sunlamp or a450W Ace Hanovia lamp for 4 to 24 hours. Solvent and isocyanide wereremoved under reduced pressure. The residue was applied to columnchromatography (silica gel, dichloromethane/methanol or hexane/acetoneor chloroform/acetone) and/or MPLC (chloroform/ethyl acetate) to givecorresponding tetracyclic intermediate 12a as illustrated in FIG. 4a.

Method A:

A solution of precursor 11a (78 mg, 0.25 mmol), phenyl isocyanide (129mg, 1.25 mmol), and hexamethylditin (123 mg, 0.375 mmol) in benzene (25mL) in a flat flask was irradiated with a 275W GE sunlamp at 80° C. for20 hours. Solvent, isocyanide, and other volatile components wereremoved under reduced pressure. The residue was applied to MPLC (EMLiChroprep Si 60, chloroform/ethyl acetate=1.8/1) to give 37 mg oftetracycle 1 2a as illustrated in FIG. 4a. The yield was 45%.

Method B:

A solution of precursor 1 la (624 mg, 2 mmol), phenyl isocyanide (309mg, 3 mmol), and hexamethylditin (982 mg, 3 mmol) in benzene (30 mL) ina flat flask was irradiated for 12 hours with a 450W Ace Hanovia lamp.After removal of solvent, isocyanide, and other volatile componentsunder reduced pressure, the residue was applied to column chromatography(silica gel, hexane/acetone 1.3:1. 1:1) to give 340 mg of crude productas brown solids. The crude product was ground with ether, filtered, andrinsed with ether to give 178 mg of tetracycle 12a as light yellowsolids. The filtrate was concentrated and applied to MPLC to giveadditional 103 mg of tetracycle 12a, in 42% total yield.

EXAMPLE 2

Following the procedure of Example 1, method A, exceptpara-methoxyphenyl isocyanide (166 mg, 1.25 mmol) was substituted forphenyl isocyanide. MPLC (chloroform/ethyl acetate 1:1) afforded 30 mg oftetracycle 12b (as shown in FIG. 4b) as off-white solids in 33% yield.¹H NMR (300 MHz, CDCl₃) δ 8.16 (1H, s), 8.03 (1H, d, J=9.3 Hz), 7.40 (1H, dd, J=9.3,2.7Hz), 7.21 (1H, d, J=1.0Hz), 7.09(1H, d, J=2.7Hz),6.58(1H, d, J=1.0 HZ), 5.15(2H, s), 3.93(3H, s), 3.69(3H, s), 3.45(1 H,t, J=7.6 Hz), 2.11 (1H, m), 1.90(1H, m), 0.93 (3H, t, J=7.3 Hz); ¹³C NMR(75 MHz, CDCl₃) δ 172.7, 161.3, 158.7, 152.7, 150.4, 146.2, 144.9,130.9, 129.4, 123.4, 129.3, 118.7, 105.4, 100.4, 96.1, 55.6, 53.2, 52.3,49.7, 25.6, 12.0; IR (neat) 1730, 1667, 1601, 1240 cm⁻¹; MS (m/e) 364(M, base peak), 336, 305, 278; HRMS calcd for C₁₂H₂₀O₄N₂ 364.1423, found364.1477.

EXAMPLE 3

Following the procedure of Example 1, method A, except para-fluorophenylisocyanide (151 mg, 1.25 mmol) was substituted for phenyl isocyanide.MPLC (chloroform/ethyl acetate 2:1) afforded 29 mg of tetracycle 12c(shown in FIG. 4c) as light yellow solids in 33% yield. ¹H NMR (300 MHz,CDCl₃) δ 8.30 (1H, s), 8.20 (1H, dd J=9.3, 5.4 Hz), 7.55 (2H, m),7.29(1H, d, J=1.3Hz), 6.63(1H, d, J=1.3Hz), 5.24(2H, s), 3.71 (3H, s),3.48 (1H, t, J=7.7.Hz), 2.16 (1H, m), 1.90 (1H, m), 0.95 (3 H, t, J=7.3Hz); ¹³C NMR (75 MHz, CDCl₃) δ 172.8, 161.3, 161.2 (J_(CF)=250.8 Hz),152.7, 152.5, 146.0, 145.7, 132.2 (J_(CF)=8.3 Hz), 130.3, 129.7, 1289(J_(CF)=10.2 Hz), 120.9 (J_(CF)=26.8 Hz), 119.6, 111.3 (J_(CF)=21.9 Hz),100.9, 53.2, 52.4, 49.7, 25.7, 12.1; IR (neat) 1732, 1659, 1599 cm⁻¹; MS(m/e) 353 (M+1), 352 (M, base peak), 324, 293, 265; HRMS calcd forC₂₀H₁₇O₃FN₂ 352.1224, found 352.1248.

EXAMPLE 4

Following the procedure of Example 1, method B. A solution of methyl2-(6-bromo-N-(2-pentyn-1 -yl)-2(1H)-pyridon-4-yl)butyrate (510 mg, 1.5mmol) prepared from 10, parafluorophenyl isocyanide (272 mg, 2.25 mmol),and hexamethylditin (737 mg, 2.25 mmol) in benzene (22.5 mL) wasirradiated for 17.5 h. Column chromatography (silica gel, hexane/acetone1.5:1,1:1) afforded 461 mg of crude product. The product was washed withether to give 142 mg of tetracycle 12d (shown in FIG. 4d) as lightyellow solids. The filtrate gave, after concentration and application toMPLC (chloroform/ethyl acetate 1.8:1), 54 mg of tetracycle 12d. Totalyield was 33%. 1H NMR (300 MHz, CDCl₃) δ 8.18 (1H, dd, J=9.2, 5.6 Hz),7.67 (1H, dd, J=9.9, 2.6 Hz), 7,54 (1H, td, J=9.2, 2.6 Hz), 7.28 (1H,s), 6.62 (1H, s), 5.19 (2H, s), 3.70 (3H, s), 3.47 (1H, t, J=7.7Hz),3.10(2H, q, J=7.6Hz), 2.14(1H, m), 1.90(1H, m), 1.36(3H, t, J=7.6 Hz),0.94 (3H, t, J=7.4 Hz); ¹³C NMR (75 MHz, CDCl₃) δ 172.7, 161.3, 161,2(J_(CF)=250.2 Hz), 152.8, 151.9, 146.4, 146.3, 144.9, 133.0(J_(CF)=9.4Hz), 127.8 (J_(CF)=12.0 Hz), 127.7, 120.2 (J_(CF)=26.3 Hz), 119.3, 107.3(J_(CF)=23.4 Hz), 100.9, 53.2, 52.3, 49.0, 25.6, 23.2, 13.8, 12.0; IR(neat) 1734, 1665, 1601 cm⁻¹; MS (m/e) 380 (M, base peak), 352, 321,294; HRMS calcd for C₂₂H₂₁O₃FN₂ 380.1536, found 380.1539.

EXAMPLES 5.1-5.3

Further examples of tetracycle analogues obtained by substitution ofvarious aryl isocyanides for phenyl isocyanide and otherwise followingthe procedure set forth in Example 1, method B, are set forth in FIGS.4e-4 g. Tetracycle 12e (shown in FIG. 4e) was obtained in 20% yield. Inthe case of the meta-substituted isocyanide reactant shown in FIG. 4f,two isomeric tetracycles 12f and 12g were obtained in a 2:1 ratio. Thecombined yield was 22%. Similarly, in the case of the meta-substitutedisocyanide reactant shown in FIG. 4g, two isomeric tetracycles 12h and12i were obtained in a 4:1 ratio. The general formula of FIG. 3illustrates such isomers as 12 and 12′. The combined yield in the caseof tetracycle 12h and 12i was 42%.

EXAMPLE 5.1

Example 1, method B was followed. A solution of 11a (156 mg, 0.5 mmol),para-trifluromethylphenylisocyanide (171 mg, 1 mmol), andhexamethyiditin (246 mg, 0.75 mmol) in benzene (10 mL) was irradiatedfor 4 to 12 h. Column chromatography (silica gel, hexane/acetone 2:1,1:1) followed by MPLC (chloroform/ethyl acetate 3.5:1) afforded 41 mg of12e in 20% yield. ¹H NMR (300 MHz, CDCl₃) δ 8.46 (1H, s), 8.33 (1H. d,J=8.9Hz), 8.23(1H, s), 7.97(1H, dd, J=8.9,1.6Hz), 7.37(1H, d, J=1.0 Hz),6.68(1H, d, J=1.0Hz), 5.29(2H, s), 3.72(3H, s), 3.50(1H, t, J=7.7 Hz),2.18 (1H, m), 1.91 (1H, m), 0.97 (3H, t, J=7.4 Hz); ¹³C NMR (125 MHz,CDCl₃) δ 172.7, 161.2, 155.1, 152.7, 149.8, 145.3, 131.9, 131.0, 131.1,129.5, (q, J_(CF)=33 Hz), 127.0, 126.2 (2 C), 123.8 (q, J_(CF)=271 Hz),120.4, 101.8, 53.2, 52.5, 49.7, 25.7, 12.1: IR (neat) 1732, 1667, 1605,1171, 1123 cm⁻¹; MS (m/e) 403, 402 (M, base peak), 383, 374, 343, 328,315.

EXAMPLE 5.2

Example 1, method B was followed. A solution of 11a (156 mg, 0.5 mmol),meta-trifluromethylphenylisocyanide (171 mg, 1 mmol), andhexamethyiditin (246 mg, 0.75 mmol) in benzene (10 mL) was irradiatedfor 12 hours. Column chromatography (silica gel, hexane/acetone 2:1,1:1)followed by MPLC (chloroform/ethyl acetate 11:1,2.5:1) afforded 31 mg of12f and 12g in 22% yield. 12f: ¹H NMR (300 MHz, CDCl₃) δ 8.67 (1H, s),8.39 (1H, d, J=8.5 Hz),8.01 (1H, d, J=7.3 Hz), 7.84 (1H, t, J=7.9 Hz),7.34 (1H, d, J=1.4 Hz), 6.67 (1H, d, J=1.4 Hz), 5.29 (2H, s), 3.72 (3H,s), 3.49 (1H, t, J=7.7 Hz), 2.17 (1H, m), 1.91 (1H, m), 0.96 (3H, t,J=7.4 Hz); ¹³C NMR (125 MHz, CDCl₃) δ 172.7, 161.2, 153.6, 152.7, 149.0,145.2, 134.5, 130.3, 128.8, 127.6, 126.7 (q, J_(CF)=31 Hz), 126.3,124.2, 124.0 (q, J_(CF)=272 Hz), 120.2, 101.5, 53.2, 52.4, 50.0, 25.7,12.1; IR (neat) 1736, 1671, 1609, 1306, 1167, 1121 cm⁻¹; MS (m/e) 403,402 (M, base peak),374, 343, 328, 315. 12 g: ¹H NMR (300 MHz, CDCl₃) δ8.53 (1H, s), 8.44 (1H, s), 8.06 (1H, d, J=8.6 Hz), 7.82 (1H, dd, J=8.6,1.4 Hz), 7.35 (1H, d, J=1.4 Hz), 6.69 (1H, d, J=1.4 Hz), 5.30 (2H, s),3.73 (3H, s), 3.50(1H, t, J=7.7Hz), 2.18(1H, m), 1.92(1H, M), 0.97(3H,t, J=7.4 Hz); ¹³C NMR (125 MHz, CDCl₃) δ 172.6, 161.2, 154.4, 152.8,147.9, 145.2, 132.2 (q, J_(CF)=33 Hz), 131.0, 130.8, 129.4 (2 C), 127.6,123.8 (q, J_(CF)=271 Hz), 123.4, 120.2, 101.7, 53.2, 52.5, 49.8, 25.7,12.1; IR (neat) 1736, 1665, 1592, 1325, 1188, 1165, 1129 cm⁻¹; MS (m/e)403, 402 (M, base peak), 383, 374, 343, 328, 315; HRMS calcd for.

EXAMPLE 5.3

Example 1, method B was followed. A solution of 11a (156 mg, 0.5 mmol),3,4-dimetholxyphenylisocyanide (163 mg, 1 mmol), and hexamethyiditin(246 mg, 0.75 mmol) in benzene (10 mL) was irradiated for 12 hours.Column chromatography (silica gel, hexane/acetone/methanol 1:1:0,1:1:0.05) followed by MPLC (chloroform/ethyl acetate/methanol 1:1:0,1:1:0.1) afforded 18 mg of 12i and 66 mg of 12h in 42% total yield. 12i:¹H NMR (300 MHz, CDCl₃) δ 8.63 (1H,s), 7.98 (1 H, d, J=9.4 Hz), 7.60(1H, d, J=9.4 Hz), 7.26 (1H, d, J=1.5 Hz), 6.62 (1H, d, J=1.5 Hz),5.24(2H, s), 4.05(6 H, s), 3.71 (3H, s), 3.47(1H, t, J=7.8 Hz), 2.16(1H, m), 1.90 (1H, m), 0.95 (3H, t, J=7.3 Hz); ¹³C NMR (125 MHz, CDCl₃)δ 6172.8, 161.4, 152.7, 151.2, 149.4, 146.1, 144.4, 142.1, 128.9, 125.8,125.0, 124.1, 119.2, 118.7, 100.7, 61.5, 56.8, 53.2, 52.4, 50.0, 25.6,12.1, IR (neat) 1732, 1662, 1595, 1267, 1169, 1096 cm⁻¹; MS (m/e) 395,394 (M, base peak), 379, 366, 335, 308; 12 h: ¹H NMR (300 MHz, CDCl₃)88.19(1H, s), 7.51 (1H, s), 7.22 (1H, d, J=1.1 Hz), 7.13 (1H, s), 6.60(1H, d, J=1.1 Hz), 5.20 (2H, s), 4.08 (3H, s), 4.06 (3H, s), 3.71 (3H,s), 6.60 (1H, d, J=1.1 Hz), 5.20 (2H, s), 4.08 (3H, s), 4.06 (3 H, s),3.71 (3H, s), 3.47(1H, t, J=7.7Hz), 2.16(1H, m), 1.90(1H, m), 0.95 (3H,t, J=7.4 Hz); ¹³C NMR (125 MHz, CDCl₃) δ 172.7, 161.4, 153.3, 152.7,150.9, 150.5, 146.5, 146.1, 128.9, 127.6, 124.3, 118.6, 107.9, 105.2,100.1, 56.3, 56.2, 53.2, 52.3, 49.8, 25.5, 12.0; IR (neat) 1736, 1667,1617, 1599, 1503, 1431, 1256, 1225 cm⁻¹; MS (m/e) 395, 394 (M, basepeak), 366, 335, 320, 308.

EXAMPLE 6.1-6.3

An interesting analogue of camptothecin potentially accessible by thepresent radical [4+1] annulation method is shown in FIG. 5. Thequinoxaline ring system of this analogue would be formed by employing anitrile (rather than an alkyne) as the radical acceptor Y in thepyridone precursor 11 of FIG. 3.

Several examples of synthesis of the requisite pyridinone precursors andthe resulting tetracycle intermediates for the analogue of FIG. 5 andrelated compounds are given below.

EXAMPLE 6.1

The precursor 11b of FIG. 6 was produced by first cooling a solution of6-bromopyridone (1.0 g, 5.75 mmol) in DME (20 mL) to −60° C. Sodiumhydride (252 mg of a 60% dispersion in oil, washed with hexanes anddried) was then added and the mixture was allowed to warm to roomtemperature. The mixture was stirred for 30 mins., until H₂ evolutionhad ceased. After this time, lithium bromide (550 mg, 6.32 mmol),bromoacetonitrile (1.38 g, 11.5 mmol) and DMF (665 μL) were added. Themixture was then heated at reflux for 16 hours. The indigo-coloredreaction mixture was then concentrated at reduced pressure and theresidue was partitioned between CH₂Cl₂ (20 mL) and water (20 mL). Theaqueous phase was further extracted with CH₂Cl₂ (3×20 mL). The combinedorganic extracts were then dried, filtered and concentrated at reducedpressure. Flash chromatography (eluant, 1:1 hexane, ethyl acetate) ofthe crude product and concentration of the fractions containing materialR_(f)=0.1 afforded the product pyridone precursor 11b as a colorlesssolid (730 mg, 64%). This material was recrystallized from CHCl₃/hexaneto afford colorless needles, mp 100-101° C. ¹H NMR (300 MHz, CDCl₃) δ7.23 (dd, J=9.3 and 7.0 Hz, 1H, H4), 6.58 (d, J=9.3 Hz, 1H), 6.56 (d,J=7.0 Hz, 1H), 5.18 (s, 2H). 13C NMR (75 MHz, CDCl₃) δ 161.66, 140.29,125.32, 119.18, 113.80, 111.98, 35.99. IR (KBr) 2999, 2961, 1660, 1583,1512, 800 cm⁻¹. MS m/e 212, 214 (M⁺), 184, 186 (M—CO), 133 (M—Br).

A solution of pyridone precursor 11b (100 mg, 0.469 mmol) in benzene (10mL) containing hexamethylditin (222 mg, 0.678 mmol) and phenylisocyanide (2.4 mL of a 1.0 M solution in benzene) was heated at 80° C.and irradiated with an hanovia UV lamp for 16 hours. After this time themixture was diluted with Et₂O and shaken with 2M HCl and then filteredthrough a sintered glass funnel. The phases were then separated and theorganic phase was extracted with 2M HCl (6×20 mL). The combined aqueousacidic phases were neutralized with NaOH and extracted with CHCl₃ (4×50mL). The combined organic phases were then dried, filtered andconcentrated at reduced pressure to afford a brown oil (110 mg).Preparative TLC of this material (1:1 acetone, CH₂Cl₂) and extraction ofthe yellow fluorescent band (Rf=0.5) gave the product tetracycle 12j asshown in FIG. 6 as a yellow solid (38 mg, 35%). ¹H NMR (300 MHz, CDCl₃)δ 8.20 (m, 2H), 7.88 (m, 2H), 7.68 (dd, J=8.7 and 7.0 Hz, 1H), 7.31 (d,J=6.7 Hz, 1H), 6.82 (d, J=8.9 Hz, 1H), 5.31 (s, 3H). ¹³C NMR (125 MHz,CDCl₃) 8161.20, 152.95, 146.65, 144.22, 142.88, 142.74, 140.14, 131.31,130.69, 129.87, 129.48, 122.25, 102.30, 50.55. IR (KBr) 3445, 2363,2340, 1653 cm⁻¹. MS m/e 235 (M⁺), 207 (M—CO).

EXAMPLE 6.2

Precursor 11 c of FIG. 7 was produced by first treating a solution ofbromopyridone (1.5 g, 6.10 mmol) in DME (20 mL) at −60° C. with sodiumhydride (267 mg of a 60% dispersion in oil). The mixture was allowed towarm to room temperature, and after evolution of hydrogen had ceasedlithium bromide (585 mg, 6.72 mmol), bromoacetonitrile (1.46 g, 12.18mmol) and DMF (720 μL) were added. The mixture was then heated at refluxfor 16 hours. After usual workup and chromatographic purification, theproduct was afforded as a colorless solid (0.98 g, 56%, 64% based onrecovered starting material). This material was recrystallized fromCHCl₃/hexanes to give colorless prisms, mp 107-109° C. ¹H NMR (300 MHz,CDCl₃) δ 6.57 (s,1H), 6.47 (s,1H), 5.15 (s, 2H), 3.74 (s, 3H), 3.43 (s,2H). ¹³C NMR (75 MHz, CDCl₃) δ 169.17, 161.17, 147.67, 125.05, 118.90,113.71, 113.58, 52.58, 40.14, 35.75. IR (KBr) 3017, 2957, 2361, 2342,1736, 1668, 1593, 1508 cm⁻¹. MS m/e 284, 286 (M⁺), 245, 247 (M—CH₂N),205 (M—Br, 100).

EXAMPLE 6.3

A solution of pyridone precursor 11c (533 mg, 1.87 mmol) in DME (8 mL)was cooled to −70° C. KO^(t)Bu (0.23 g, 2.05 mmol) was added in oneportion, and the solution immediately turned a bright yellow color.After 5 mins., ethyl iodide (0.62 g, 7.75 mmol) was added and thereaction mixture was stirred for 2 hours at −70° C. and then at roomtemperature for 20 hours. After this time the mixture was poured intowater (20 mL) and extracted with CH₂Cl₂ (3×20 mL). The combined extractswere dried, filtered and then concentrated at reduced pressure. Theresidue obtained was purified by flash chromatography (eluant, 1:1 ethylacetate, CHCl₃) to afford the product 11d of FIG. 8 as a colorless oilthat solidified on standing (400 mg, 65%). This precursor lid wasrecrystallized from CHCl₃hexanes to afford colorless prisms. ¹H NMR (300MHz, CDCl₃) δ 6.55 (s,1H), 6.42 (s, 1H), 5.12 (s, 2H), 3.66 (s, 3H),3.21 (t, J=7.6 Hz, 1H), 1.97 (m, 1H), 1.68 (m,1H), 0.87 (t, J=7.3 Hz,3H). ¹³C NMR (75 MHz, CDCl₃) δ 171.71, 161.11, 152.28, 125.07, 117.60,113.72, 111.84, 52.26, 35.69, 32.52, 25.08, 11.68. IR (NaCl) 2967, 2359,1736, 1671, 1597, 1200, 1169 cm⁻¹, MS m/e 314, 316 (M⁺), 233 (M—Br,100).

According to FIG. 8, a solution of the bromopyridinone precursor 11d(120 mg, 0.383 mmol), phenyl isocyanide (2.0 mL of a 1.0 M solution inbenzene) and hexamethylditin (180 mg) in benzene (10 mL) was heated at80° C. and irradiated with a Hanovia lamp for 20 hours. The mixture wasthen concentrated and the residue was purified by flash chromatography,(EtOAc/CHCl₃, 1:1). Fractions containing fluorescent material, R_(t)=0.3were combined and concentrated to afford product tetracycle 12k as ayellow solid (14 mg, 11%). ¹H NMR (300 MHz, CDCl₃) δ 8.20 (m, 2H), 7.88(m, 2H), 7.35 (s,1H), 6.71 (s, 1H), 5.28 (s, 2H), 3.73 (s, 3H), 3.49 (t,J=7.6 Hz, 1H), 2.16 (m, 1H), 1.90 (m, 1H), 0.97 (t, J=7.3 Hz, 3H). ¹³CNMR (125 MHz, CDCl₃) δ 172.65, 160.95, 153.10, 152.42, 146.51, 143.94,142.84, 142.74, 131.38, 130.95, 129.89, 129.48, 121.05, 102.37, 53.19,52.50, 0.37, 25.64 (one resonance not observed). IR (NaCl) 2973, 2386,1738, 1659, 1651, 1622 cm⁻¹. MS m/e 335 (M⁺, 100), 307 (M—CO), 276M—CO₂Me).

Preparation of Aryl Isocyanides

The aryl isocyanides (e.g., phenyl isocyanide) for reaction withprecursor 11 in the present synthesis are readily available from arylamines by several standard methods as illustrated in FIG. 9. Typically,amines are reacted with base and chloroform (Method A of FIG. 9) or theyare first converted to the respective formamides which are thendehydrated (Method B of FIG. 9). See Ugi, I., “Isonitrile Chemistry,”Academic Press, NY, 10-17 (1971) and Walborsky, H., Org. Prep. Proced.Int., 11, 293-311 (1979), the disclosure of which are incorporatedherein by reference.

Reaction of Aryl Isocyanides with Precursor 11

The reaction of precursor 11 with an aryl isocyanide to produce atetracycle intermediate preferably takes place in the presence of acoreactant of the general formula given below:

R₃M—MR₃

In the above general formula, M comprises a metal or metalloid.Preferably M comprises Si, Ge or Sn. Most preferably M comprises Sn. Rmay comprise an alkyl or aryl group. Preferably the coreactant compriseshexamethylditin.

Several examples of the reaction of precursor 11a and phenyl isocyanideare given in Table 1 for hexabutyiditin (Bu₃Sn)₂, hexamethyidisilane(Me₃Si)₂ and hexamethyiditin (Me₃Sn)₂. The percent yields in Table 1 arefor tetracycle intermediate 12a.

TABLE 1 Coreactant Phenyl isocyanide Temp. Time Yield [1] 1.5 eq(Bu₃Sn)₂   5 eq 80° C. 24 hr. 48% 1.5 eq (Bu₃Sn)₂ 1.5 eq RT 24 hr. 35%[2] 1.5 eq (Me₃Si)₂   5 eq 80° C. 24 hr. 45% 1.5 eq (Me₃Si)₂ 1.5 eq RT24 hr. 28% [3] 1.5 eq (Me₃Sn)₂   5 eq 80° C. 36 hr. 58% 1.5 eq (Me₃Sn)₂1.5 eq RT 52 hr. 56%

Metal or metalloid hydrides may also be used as a coreactant.

While presently preferred embodiments of the present invention have beendescribed in detail, the invention may be otherwise embodied within thescope of the appended claims.

What is claimed is:
 1. A chemical compound having the formula

wherein Y is —CR³, R¹ is an allyl group, a benzyl group, a propargylgroup, an alkoxyl group, a halogen, a haloalkyl group, an amino group,or a cyano group, R², R³ and R⁶ are, independently, hydrogen, an allylgroup, a benzyl group, a propargyl group, an alkoxyl group, a halogen, ahaloalkyl group, an amino group, or a cyano group, R⁴ is an alkyl group,an allyl group, a propargyl group or a benzyl group, and R⁵ is an alkylgroup, or a benzyl group.
 2. The chemical compound of claim 1 wherein R⁴is an ethyl group.
 3. The chemical compound of claim 1 wherein R⁵ is amethyl group.
 4. The chemical compound of claim 1 wherein R¹ is —F,—OCH₃ or —CF₃.
 5. The chemical compound of claim 1 wherein R² is —H, —F,—OCH₃ or —CF₃.
 6. A chemical compound having the formula

wherein Y is —CR³, R⁶ is an allyl group, a benzyl group, a propargylgroup, an alkoxyl group, a halogen, a haloalkyl group, an amino group,or a cyano group, R¹, R², and R³ are, independently, hydrogen, an allylgroup, a benzyl group, a propargyl group, an alkoxyl group, a halogen, ahaloalkyl group, an amino group, or a cyano group, R⁴ is an alkyl group,an allyl group, a propargyl group or a benzyl group, and R⁵ is an alkylgroup, or a benzyl group.
 7. The chemical compound of claim 1 wherein R⁵is a C₁-C₆ alkyl group.
 8. A chemical compound having the formula

wherein Y is —CR³, R² is an allyl group, a benzyl group, a propargylgroup, an alkoxyl group, a halogen, a haloalkyl group an amino group, ora cyano group, R¹, R³ and R⁶ are, independently, hydrogen, an allylgroup, a benzyl group, a propargyl group, an alkoxyl group, a halogen, ahaloalkyl group, an amino group, or a cyano group, R⁴ is an alkyl group,an allyl group, a propargyl group or a benzyl group, and R⁵ is an alkylgroup, or a benzyl group.
 9. The chemical compound of claim 8 wherein R⁴is an ethyl group.
 10. The chemical compound of claim 8 wherein R⁵ is amethyl group.
 11. The chemical compound of claim 8 wherein R¹ is —H, —F,—OCH₃ or —CF₃.
 12. The chemical compound of claim 8 wherein R² is —F,—OCH₃ or —CF₃.
 13. The chemical compound of claim 8 wherein R⁶ is —H,—F, —OCH₃ or —CF₃.
 14. The chemical compound of claim 8 wherein R⁵ is aC₁-C₆ alkyl group.
 15. A chemical compound having the formula

wherein Y is —CR³, R³ is an allyl group, a benzyl group, a propargylgroup, an alkoxyl group, a halogen, a haloalkyl group, an amino group,or a cyano group, R¹, R², and R⁶ are, independently, hydrogen, an allylgroup, a benzyl group, a propargyl group, an alkoxyl group, a halogen, ahaloalkyl group, an amino group, or a cyano group, R⁴ is an alkyl group,an allyl group, a propargyl group or a benzyl group, and R⁵ is an alkylgroup, or a benzyl group.
 16. The chemical compound of claim 15 whereinR⁴ is an ethyl group.
 17. The chemical compound of claim 15 wherein R⁵is a methyl group.
 18. The chemical compound of claim 15 wherein R¹ is—H, —F, —OCH₃ or —CF₃.
 19. The chemical compound of claim 15 wherein R²is —H, —F, —OCH₃ or —CF₃.
 20. The chemical compound of claim 15 whereinR⁶ is —H, —F, —OCH₃ or —CF₃.
 21. The chemical compound of claim 15wherein R⁵ is a C₁-C₆ alkyl group.
 22. The chemical compound of claim 6wherein R⁶ is —F, —OCH₃ or —CF₃.
 23. The chemical compound of claim 6wherein R⁴ is an ethyl group.
 24. The chemical compound of claim 6wherein R⁵ is a methyl group.
 25. The chemical compound of claim 6wherein R¹ is —H, —F, —OCH₃ or —CF₃.
 26. The chemical compound of claim6 wherein is —H, —F, —OCH₃ or —CF₃.
 27. The chemical compound of claim 6wherein R⁵ is a C₁-C₆ alkyl group.